Shear stress is the frictional force produced by the flow of blood at the endothelial surface and is a critical determinant of arterial structure and biology. While physiological levels are associated with arterial health, both low and high levels of shear stress produce changes in vascular phenotype that may be relevant to cardiovascular disease. Chronically elevated shear stress stimulates arterial growth and increases lumen size. In general, this outward remodeling continues until shear stress is restored to baseline, thus providing an important homeostatic mechanism. This response contributes to normal development, the compensatory response to growing atherosclerotic plaques (Glagov Phenomenon), and collateral development. Experimental studies have shown that elevated shear stress activates the PIS kinase/Akt system in endothelial cells leading to activation and increased expression of endothelial nitric oxide synthase (eNOS) and growth and remodeling of the arterial wall. Despite their potential clinical relevance, few studies have translated these experimental findings to humans. Our preliminary data show that removal of the radial artery for use as a bypass conduit produces a marked increase in ulnar artery flow as it accommodates the required supply of blood to the hand. This flow increase is associated with a remodeling response over the next eight weeks that varies among individuals. We propose to investigate local and systemic determinants of this remodeling response. In Aim 1. we will characterize the changes in ulnar artery geometry and function produced by a chronic increase in shear stress in humans. In Aim 2. we will relate local and systemic factors measured at baseline to outward remodeling response of the ulnar artery. In this regard, we will assess systemic risk factors, matrix metalloproteinases, circulating endothelial progenitor cells, and non-invasive measures of vascular function. We will also investigate specific signaling pathways in isolated segments of radial artery. In Aim 3, we will complete intervention studies to probe potential mechanisms (loss of endothelium-derived NO and mitochondria! dysfunction) that may account for impaired outward remodeling in patients with coronary artery disease. This proposal takes advantage of a unique clinical situation to study outward remodeling in humans, and we suggest that these studies will yield important new information that is relevant to the management of patients with vascular disease.